Mg Marrosu

Refining genetic associations in multiple sclerosis

Genome-wide association studies involve several hundred thousand markers and, even when quality control is scrupulous, are invariably confounded by residual uncorrected errors that can falsely inflate the apparent difference between cases and controls (so-called genomic inflation). As a consequence such studies inevitably generate false positives alongside genuine associations. By use of Bayesian logic and empirical data, the Wellcome Trust Case Control Consortium suggested that association studies in complex disease should involve at least 2000 cases and 2000 controls, at which level they predicted that p values of less than 5×10 −7 would more commonly signify true positives than false positives.

Familial effects on the clinical course of multiple sclerosis

Background: Familial factors influence susceptibility to multiple sclerosis (MS) but it is unknown whether there are additional effects on the natural history of the disease. Method: We evaluated 1,083 families with ≥2 first-degree relatives with MS for concordance of age at onset, clinical course, and disease severity and investigated transmission patterns of these clinical features in affected parent-child pairs. Results: There is concordance for age at onset for all families (correlation coefficient 0.14; p < 0.001), as well as for affected siblings (correlation coefficient 0.15; p < 0.001), and affected parent-child pairs (correlation coefficient 0.12; p = 0.03) when each is evaluated separately. Concordance for year of onset is present among affected siblings (correlation coefficient 0.18; p < 0.001) but not the parent-child group (correlation coefficient 0.08; p = 0.15). The clinical course is similar between siblings (kappa 0.12; p < 0.001) but not affected parents and their children (kappa −0.04; p = 0.09). This influence on the natural history is present in all clinical subgroups of relapsing-remitting, and primary and secondary progressive MS, reflecting a familial effect on episodic and progressive phases of the disease. There is no concordance for disease severity within any of the considered family groups (correlation coefficients: all families analyzed together, 0.02, p = 0.53; affected sibling group, 0.02, p = 0.61; affected parent-child group, 0.02, p = 0.69). Furthermore, there are no apparent transmission patterns of any of the investigated clinical features in affected parent–child pairs and no evidence for anticipation or effects of genetic loading. Conclusion: Familial factors do not significantly affect eventual disease severity. However, they increase the probability of a progressive clinical course, either from onset or after a phase of relapsing remitting disease. The familial effect is more likely to reflect genetic than environmental conditions. The results are relevant for counseling patients and have implications for the design of studies seeking to identify factors that influence the natural history of the disease.

Age at onset in multiple sclerosis

Abstract Age at onset of multiple sclerosis (MS) can vary from childhood to adult life. Many reports have been carried out over the years concerning the role of age at onset in determining the disease outcome. In a sporadic MS population of 1463 patients with homogeneous clinical and demographic features, derived from three Italian neurological centres (Bari, Cagliari and Sassari), we analysed the relative weights of current age and age at onset on disease severity according to the expanded disability status scale (EDSS) score, by fixing the disease duration.The results of present study demonstrate that clinical disability in MS in influenced by the patients age (p<0.01) and not by the age at onset. Therefore, these data do not confirm the hypothesis that an early age at onset should be considered a favourable prognostic factor of the disease outcome.

Bias in parental transmission of the HLA-DR3 allele in Sardinian multiple sclerosis

The authors analyzed the female: male (F:M) ratio according to the HLA-DRB1-DQB1 genotype in a cohort of multiple sclerosis (MS) patients from Sardinia, where the disease is associated with DR3 and DR4. In the whole cohort of 1,097 patients, F:M ratio was 2.24; however, it was 2.88 in DR3/DR3 and 2.52 in DR3/DRX (X#DR3 and DR4) individuals. Parental transmission of DR3 and DR4, assessed in a set of 565 case-parent triads, showed evidence of paternal inheritance of DR3 in affected women, thus explaining the excess of females in the DR3 category.

‘Timed up and go’ and brain atrophy: a preliminary MRI study to assess functional mobility performance in multiple sclerosis

Motor and cognitive disabilities are related to brain atrophy in multiple sclerosis (MS). ‘Timed up and go’ (TUG) has been recently tested in MS as functional mobility test, as it is able to evaluate ambulation/coordination-related tasks, as well as cognitive function related to mobility. The objective of this study is to evaluate the relationship between brain volumes and TUG performances. Inclusion criteria were a diagnosis of MS and the ability to walk at least 20xa0m. TUG was performed using a wearable inertial sensor. Times and velocities of TUG sub-phases were calculated by processing trunk acceleration data. Patients underwent to a brain MRI, and volumes of whole brain, white matter (WM), grey matter (GM), and cortical GM (C) were estimated with SIENAX. Sixty patients were enrolled. Mean age was 41.5xa0±xa011.6xa0years and mean EDSS 2.3xa0±xa01.2. Total TUG duration was correlated to lower WM (ρxa0=xa00.358, pxa0=xa00.005) and GM (ρxa0=xa00.309, pxa0=xa00.017) volumes. A stronger association with lower GM volume was observed for intermediate (ρxa0=xa00.427, pxa0=xa00.001) and final turning (ρxa0=xa00.390, pxa0=xa00.002). TUG is a useful tool in a clinical setting as it can not only evaluate patients’ disability in terms of impaired functional mobility, but also estimate pathological features, such as grey atrophy.

Is multiple sclerosis severity a genetically influenced trait

Abstract Multiple sclerosis (MS), an inflammatory demyelinating disease of the central nervous system of unknown pathogenesis, is a complex disease with a multifactorial etiology determined by both genetic and environmental factors. The pathological entity MS has a wide phenotype, and also the severity of the disease is widely variable. Clinical heterogeneity of the disease might arise from different genotype-phenotype interactions. Results of recent studies and theories about the modifying role of different genes in the course and the severity of MS are here discussed.